The present invention relates generally to stents which are implantable or deployable in a vessel or duct within the body of a patient to maintain the lumen of the duct or vessel open, and more particularly to improvements in stent coatings and in methods for applying such coatings.
When inserted and deployed in a vessel, duct or tract of the body, for example a coronary artery after dilatation of the artery by balloon angioplasty, a stent acts as a prosthesis to maintain the vessel, duct or tract (generally referred to as a vessel for convenience herein) open. The stent has the form of an open-ended tubular element with openings through its sidewall to enable its expansion from a first outside diameter which is sufficiently small to allow the stent to traverse the vessel to reach a site where it is to be deployed, to a second outside diameter sufficiently large to engage the inner lining of the vessel for retention at the site.
An occluded coronary artery, for example, is typically attributable to a buildup of fatty deposits or plaque on the inner lining of the vessel. A balloon angioplasty procedure is the treatment of choice to compress the deposits against the inner lining of the vessel to open the lumen. Alternatively, removal of plaque may be achieved. by laser angioplasty, or by rotationally cutting the material into finely divided particles which are dispersed in the blood stream. The problem with angioplasty for a large segment of cardiac patients is that a new blockage appears within only weeks after the angioplasty procedure, attributable to trauma to the blood vessel wall from the angioplasty. The mechanism responsible for the new blockage is intimal hyperplasia, i.e., a rapid proliferation of smooth muscle cells in the affected region of the wall. Thus, many patients suffer restenosis, or re-occlusion of the vessel lumen.
The customary procedure is to install a stent at the trauma site at the time of or shortly after the angioplasty is performed. The stent is deployed by radial expansion under outwardly directed radial pressure exerted, for example, by active inflation of a balloon of a balloon catheter on which the stent is mounted. In some instances, passive spring characteristics of a pre-formed elastic stent serves the purpose. The stent is thus expanded to engage the inner lining or inwardly facing surface of the vessel wall with sufficient resilience to allow some contraction but also with sufficient stiffness to largely resist the natural recoil of the vessel wall.
The presence of the stent in the vessel, however, tends to promote thrombus formation as blood flows through the vessel, which results in an acute blockage. The thrombosis and clotting can be reduced or even eliminated by localized application of appropriate anti-thrombus or anti-clotting drugs in a biodegradable formulation, which act for a period of time sufficient to achieve this purpose. Some difficulty is encountered in providing a stent surface which is suitable for retention of the necessary drug(s).
At the outward facing surface of the stent in contact or engagement with the inner lining of the vessel, tissue irritation can exacerbate the same type of trauma that occurs during an angioplasty procedure, and possible restenosis. It is desirable to provide a timed release of anti-fibrotic drug(s) from the stent surface to avoid hyperplasia and recurrence of blockage at the stent site.
Another factor affecting the choice of the stent and the stent material is the possibility of allergic reaction of the patient to the stent implant. Biomaterial coatings can be helpful, but a statistically significant percentage of patients are allergic to materials of which some stents are composed, including chrome, nickel, and medical grade 316L stainless steel, which contains about 20% nickel. For such patients, the allergic reaction may be sufficient that stent implant is contraindicated. Wholly biodegradable stents of possibly sufficient radial strength are currently undergoing tests and may prove suitable in such cases.
It is essential that the implanting surgeon be able to see the progress of the stent as it is being inserted into place at the desired target site in the body, and for purposes of examination from time to time thereafter at the implant site, typically by X-ray fluoroscopy. The wall of the stent must be sufficiently thick to withstand the vessel wall recoil after deployment at the target site, but to allow the stent to be seen on the fluoroscope. Various materials, such as 316L stainless steel, possess suitable mechanical strength. Typical stent wall or wire thicknesses have ranged from 70 to 200 microns (or micrometers, xcexcm). A 70 to 80 xcexcm 316L steel stent offers sufficient strength to resist recoil so as to maintain a lumen diameter close to the diameter achieved at full deployment by balloon inflation. This relatively thin and tiny metal structure creates little shadow on a fluoroscopic picture, however, since the X-ray absorption of the metal is low. Increasing the wall thickness of the stent to enhance its radiopacity makes the stent less flexible, which makes it more difficult to maneuver the stent through narrow vessels. Greater wall thickness also makes it necessary to apply a larger radial force by balloon inflation during deployment of the stent, with concomitant increased risk of balloon rupture.
It follows that a suitable stent should possess at least the features of flexibility, resistance to vessel recoil, successful interventional placement, good radiopacity, sufficient thinness to minimize obstruction in the vessel being held open, and avoidance of vessel re-occlusion. Stent design plays an important role in influencing these features, together with proper selection or fabrication of the material of which the stent is composed.
Aside from vascular usage, other ducts or tracts of the human body in which a stent might be installed to maintain an open lumen include the tracheo-bronchial system, the biliary hepatic system, the esophageal bowel system, and the urinary tract. Many of the same requirements are found in these other endoluminal usages of stents.
Despite improvements in the design and construction of coronary stents, restenosis remains a problem. One major contributing factor is the inability of the body to incorporate the implanted foreign material quickly. Basic research with cell cultures and animal experiments have demonstrated that the degree of endothelialization of the foreign body determines the amount of the restenosis. Although an assumption among industry practitioners and researchers has been that a highly polished and smooth surface is beneficial to prevent stent thrombosis and to facilitate endothelialization, experiments have indicated that this is not entirely true.
A significant reason for the lack of a high clinical success rate with electropolished stents is the fact that the smooth muscle cells which seek to envelop a foreign body, such as a stent strut into the vessel wall, require a higher degree of proliferation to cover the foreign body. The continuing flow of blood with a high pressure and high shearing stress prevents the migration of smooth muscle cells, which proliferate from the media and adventitial cells of a stented vessel such as a coronary artery. It has been shown that a slightly rough surface considerably facilitates the coverage by smooth muscle cells, leading to a functional endothelial layer even after 10 to 14 days after stent implantation. A single layer of endothelial cells has been found to seal the neointima and thereby prevent the stimulus which facilitates and enhances the proliferation of cells beyond mere coverage of the foreign body.
The thinner the stent strut, the less the lumen of the stented vessel is obstructed. Moreover, a thin stent is more easily covered by a neoendothelial build-up. Accordingly, it is desirable to make the stent wall as thin as can be practically achieved. But the fluoroscopic visibility of stainless steel in a thickness below 60 xcexcm is very poor because of the limited extinction of x-rays by such a thin metal tube.
The ""045 patent discloses a vascular or endoluminal stent, composed of medical grade implantable 316L stainless steel, for example, which is covered with a very thin, highly adherent layer of gold or other noble metal, such as platinum, or an alloy which is primarily gold or other noble metal, or other metal having a high Z-number. Since gold has a six times (6xc3x97) higher radiopacity than stainless steel, a 10 xcexcm layer of gold provides fluoroscopic visualization equivalent to 60 xcexcm thickness of stainless steel. Thus, a gold coating, for example, offers a radiopaque surface that renders the stent highly visible under fluoroscopy as it is being advanced through the vessel lumen to the desired site of deployment, as well as after deployment. Such a coating may be provided in a very thin layer, so that the stent wall thickness is determined almost solely by considerations of mechanical strength, with consequent reduction of stent external diameter over what would be required if enhanced radiopacity of the base metal were an overriding factor.
The noble metal layer may be ultra-thin and is applied to cover the entire stentxe2x80x94interior as well as exterior surfaces and all edges bounding the internal openings in the wall and the ends thereof if the stent is of the hollow, open-ended tube type, or the entire surface of the wire if the stent is of the wire type. The layer is applied in a wayxe2x80x94including a two-layer applicationxe2x80x94to assure an absolute adherence to the underlying metal of the stent and thereby to prevent even any cracking or defects in the homogeneous nobler metal layer, much less resist peeling or flaking of the layer during insertion, and especially during expansion of the diameter of the stent as it is being deployed in final position in the artery at the target site.
As pointed out in the ""045 patent, gold is non-irritating and substantially non-allergenic, which allows a gold-plated stent to be implanted even in patients with severe materials allergies. Additionally, the gold layer offers a surface of substantially non-thrombogenic characteristics, and therefore reduces the likelihood of an acute closure of the vessel in which it is implanted. And if an acute closure is avoided, it is much more likely that a chronic closure of the lumen will be avoided in the region of the vessel occupied by the stent. A gold-coated stent exhibits about 40% or less thrombus formation than that of uncoated metal stents, especially steel.
The disadvantage of reduced mechanical strength of noble metals such as gold or platinumxe2x80x94which makes them unsuitable if sought to be used alone for application in the human vascular systemxe2x80x94is overcome by the use of a core composed of a material such as stainless steel, having considerably better mechanical properties than the noble metal. And the presence of an uninterrupted (i.e., without cracks or related defects), substantially uniform, homogeneous coating of gold or other noble metal has been found to be of great importance to avoid a galvanic potential which could ultimately lead to corrosion of the underlying steel or lesser metal. Such a corrosive environment is unacceptable in a stent to be permanently implanted in the body. The highly adherent noble metal coating provides long-term stability and excellent clinical results, and its relatively softer constituency compared to the underlying rigid core of the stent allows at least a slight configurational change upon expansion of the stent to its fully deployed state.
The ""045 patent describes a preferred application of an initial layer of gold by vaporization in a vacuum chamber and then accelerating the gold ions onto and in adherent relationship with the surface of the underlying metal, with stable anchoring thereto, to a thickness of 1 xcexcm or more, followed by a galvanic process to provide a relatively uniform, overall layer thickness of from about 3 to about 6 xcexcm including the initial foundation layer. This achieves a highly adherent, tight coverage, and firm, yet lineally extensible, bond between the base metal of the stent core or carrier and the noble metal of the outer layer.
The co-pending ""053 application describes, in a preferred embodiment, a stent whose sidewall includes a first solid layer or thickness of a biocompatible base metal, and a second porous layer or thickness which is composed of spherically-shaped metal particles, composed at least in part of a noble metal, which are bonded together to leave spaces between the particles which may serve as a repository for drugs to assist in maintaining the lumen of the vessel open. The second thickness overlies the first thickness in tightly adherent relation thereto, and has a radiopacity which substantially exceeds that of the first thickness.
An embodiment of a stent described in the ""053 application includes at least one drug selected from a group consisting of anti-thrombotic, anti-platelet, anti-inflammatory and anti-proliferative drugs, residing in the repository. A biodegradable carrier retains the drugs for timed release from the repository when the stent is deployed at the selected implant site in the blood vessel. Alternatively, the spacing of the metal particles may be such to provide a timed release of the drugs from the repository. Preferably, the particles are located with larger diameter sizes adjacent and bonded to the surface of the first thickness and with progressively smaller diameter sizes bonded together up to the outermost region of the second thickness. In either event, the anti-platelet and/or anti-thrombotic drugs are preferably infused into the porous layer repository, i.e., into the spaces or interstices between the particles, existing at the inward facing surface (and if desired, at directly adjacent edges of the openings) of the stent to inhibit clogging of the lumen as a result of interaction between the stent itself and the blood flow therethrough. The anti-inflammatory and/or anti-proliferative drugs are preferably infused into the repository existing at the outward facing surface (and if desired, at directly adjacent edges of the openings) of the stent to inhibit restenosis as a result of fibrosis or proliferation of tissue from trauma to the inner lining of the vessel arising from contact with the stent.
The ""053 application also describes a third layer of a ceramic-like materialxe2x80x94preferably of either iridium oxide or titanium nitratexe2x80x94which is applied as a coating overlying exposed surfaces of the metal particles in tightly adherent relation to the second thickness at those surfaces, without filling or blocking the spaces between the particles, so that the repository for drugs originally formed in the second layer remains available. The desired drugs may be infused into spaces between particles, in preferential locations as noted above, for retention and dispensing in the same manner as if the third layer had not been applied. Additionally, the ceramic-like material is resistant to tissue irritation to further avoid traumatic response during contact of the stent with the inner lining of the vessel at the implant site.
The base metal may be 316L stainless steel, chromium, nickel, titanium, iridium, or nitinol, for example, nominally of 70 xcexcm thickness. The metal particles of platinum-iridium alloy have diameters ranging from about 50 to 500 nanometers (nm), and the porous layer is applied atop the base metal to a thickness in a range from about 4 to 8 xcexcm. The iridium oxide or titanium nitrate is coated on surfaces of the metal particles to a thickness in a range from approximately 50 to 500 nm. The desired drugs or other selected agents are infused into the reservoir provided by the voids or interstices between particles of the porous layer. Timed release of the drugs may be achieved by incorporating them in a biodegradable carrier.
The ""561 patent also discloses use of a stent structure having three fundamental layers, a first underlying layer of a base metal that functions to provide high mechanical strength, a second intermediate layer that functions to provide high fluoroscopic visibilityxe2x80x94preferably a noble metal layer or alloy thereofxe2x80x94, and a top layer of a particularly beneficial biocompatible materialxe2x80x94preferably a ceramic-like material such as iridium oxide or titanium nitrate. The intermediate layer of elemental or alloy of a noble metal is uninterrupted, highly adherent for tight coverage and substantially uniform thickness. Such an intermediate layer tends to assure avoidance of a galvanic potential that would lead to corrosion of the lesser, base metal, including such a condition that may obtain with a layer of ceramic-like metal overlying the base metal at points where fissures might exist were it not for the uninterrupted presence of the intermediate noble metal layer. The three layer stent of the ""561 patent exhibits mechanical strength, small physical dimensions, increased visibility, long-term stability, and a highly biocompatible surface that enables rapid endothelialization with low occurrence of restenosis.
Gene therapy or transfer is used as an alternative to drugs to inhibit proliferation of smooth muscle cells, to prevent restenosis that could block the lumen of the vessel in which the stent is deployed. In this technique, a viral vector transfers at least part of the genetic information of interest to the target cell. A gene transfer agent constituting the viral vector or virus is incorporated in a biodegradable carrier, or microspheres or liposomes as the viral vector are contained in solution, and the combination is infused into the reservoir of the multilayer stent from which it is released in a substantially programmed manner.
The present invention provides a stent having a tubular metal base adapted to be expanded from a first vessel-navigable diameter to a larger second vessel-deployed diameter. A thin, continuous intermediate layer of noble metal or alloy thereof selected from a group consisting of niobium, zirconium, titanium and tantalum, is applied or deposited to overlie and tightly adhere to an exposed surface area of the tubular metal base. Then, a biocompatible outer layer of iridium oxide is applied to overlie and adhere to the intermediate layer. The outer layer has a relatively rough surface with interstices into which beneficial drugs or other substances or agents may be infused, with or without a biodegradable carrier, to preclude occlusion from restenosis or thrombosis during the acute stage following deployment of the stent.